George Sgouros

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (226)1046.33 Total impact

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    ABSTRACT: Red bone marrow (RBM) toxicity is dose-limiting in (pretargeted) radioimmunotherapy (RIT). Previous blood-based and two-dimensional (2D) image-based methods have failed to show a clear dose-response relationship. We developed a three-dimensional (3D) image-based RBM dosimetry approach using the Monte Carlo-based 3D radiobiological dosimetry (3D-RD) software and determined its additional value for predicting RBM toxicity. RBM doses were calculated for 13 colorectal cancer patients after pretargeted RIT with the two-step administration of an anti-CEA × anti-HSG bispecific monoclonal antibody and a 177Lu-labeled di-HSG-peptide. 3D-RD RBM dosimetry was based on the lumbar vertebrae, delineated on single photon emission computed tomography (SPECT) scans acquired directly, 3, 24, and 72 h after 177Lu administration. RBM doses were correlated to hematologic effects, according to NCI-CTC v3 and compared with conventional 2D cranium-based and blood-based dosimetry results. Tumor doses were calculated with 3D-RD, which has not been possible with 2D dosimetry. Tumor-to-RBM dose ratios were calculated and compared for 177Lu-based pretargeted RIT and simulated pretargeted RIT with 90Y. 3D-RD RBM doses of all seven patients who developed thrombocytopenia were higher (range 0.43 to 0.97 Gy) than that of the six patients without thrombocytopenia (range 0.12 to 0.39 Gy), except in one patient (0.47 Gy) without thrombocytopenia but with grade 2 leucopenia. Blood and 2D image-based RBM doses for patients with grade 1 to 2 thrombocytopenia were in the same range as in patients without thrombocytopenia (0.14 to 0.29 and 0.11 to 0.26 Gy, respectively). Blood-based RBM doses for two grade 3 to 4 patients were higher (0.66 and 0.51 Gy, respectively) than the others, and the cranium-based dose of only the grade 4 patient was higher (0.34 Gy). Tumor-to-RBM dose ratios would increase by 25% on average when treating with 90Y instead of 177Lu. 3D dosimetry identifies patients at risk of developing any grade of RBM toxicity more accurately than blood- or 2D image-based methods. It has the added value to enable calculation of tumor-to-RBM dose ratios.
    Full-text · Article · Dec 2015
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    ABSTRACT: The programmed cell death ligand 1 (PD-L1) participates in an immune checkpoint system involved in preventing autoimmunity. PD-L1 is expressed on tumor cells, tumor-associated macrophages, and other cells in the tumor microenvironment. Anti-PD-L1 antibodies are active against a variety of cancers, and combined anti-PD-L1 therapy with external beam radiotherapy has been shown to increase therapeutic efficacy. PD-L1 expression status is an important indicator of prognosis and therapy responsiveness, but methods to precisely capture the dynamics of PD-L1 expression in the tumor microenvironment are still limited. In this study, we developed a murine anti-PD-L1 antibody conjugated to the radioactive isotope Indium-111 (111In) for imaging and biodistribution studies in an immune-intact mouse model of breast cancer. The distribution of 111In-DTPA-anti-PD-L1 in tumors as well as the spleen, liver, thymus, heart, and lungs peaked 72 hours after injection. Co-injection of labeled and 100-fold unlabeled antibody significantly reduced spleen uptake at 24 hours, indicating that an excess of unlabeled antibody effectively blocked PD-L1 sites in the spleen, thus shifting the concentration of 111In-DTPA-anti-PD-L1 into the blood stream and potentially increasing tumor uptake. Clearance of 111In-DTPA-anti-PD-L1 from all organs occurred at 144 hours. Moreover, dosimetry calculations revealed that radionuclide-labeled anti-PD-L1 antibody yielded tolerable projected marrow doses, further supporting its use for radiopharmaceutical therapy. Taken together, these studies demonstrate the feasibility of using anti-PD-L1 antibody for radionuclide imaging and radioimmunotherapy, and highlight a new opportunity to optimize and monitor the efficacy of immune checkpoint inhibition therapy.
    Full-text · Article · Nov 2015 · Cancer Research

  • No preview · Conference Paper · Nov 2015
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    ABSTRACT: Purpose: Dosimetric accuracy depends directly upon the accuracy of the activity measurements in tumors and organs. The authors present the methods and results of a retrospective tumor dosimetry analysis in 14 patients with a total of 28 tumors treated with high activities of 153Sm-ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) for therapy of metastatic osteosarcoma using planar images and compare the results with three-dimensional dosimetry. Materials and Methods: Analysis of phantom data provided a complete set of parameters for dosimetric calculations, including buildup factor, attenuation coefficient, and camera dead-time compensation. The latter was obtained using a previously developed methodology that accounts for the relative motion of the camera and patient during whole-body (WB) imaging. Tumor activity values calculated from the anterior and posterior views of WB planar images of patients treated with 153Sm-EDTMP for pediatric osteosarcoma were compared with the geometric mean value. The mean activities were integrated over time and tumor-absorbed doses were calculated using the software package OLINDA/EXM. Results: The authors found that it was necessary to employ the dead-time correction algorithm to prevent measured tumor activity half-lives from often exceeding the physical decay half-life of 153Sm. Measured half-lives so long are unquestionably in error. Tumor-absorbed doses varied between 0.0022 and 0.27cGy/MBq with an average of 0.065cGy/MBq; however, a comparison with absorbed dose values derived from a three-dimensional analysis for the same tumors showed no correlation; moreover, the ratio of three-dimensional absorbed dose value to planar absorbed dose value was 2.19. From the anterior and posterior activity comparisons, the order of clinical uncertainty for activity and dose calculations from WB planar images, with the present methodology, is hypothesized to be about 70%. Conclusion: The dosimetric results from clinical patient data indicate that absolute planar dosimetry is unreliable and dosimetry using three-dimensional imaging is preferable, particularly for tumors, except perhaps for the most sophisticated planar methods. The relative activity and patient kinetics derived from planar imaging show a greater level of reliability than the dosimetry.
    No preview · Article · Nov 2015 · Cancer Biotherapy and Radiopharmaceuticals
  • J. Yue · E.C. Frey · T. Mauxion · A. Josefsson · G. Sgouros · R.F. Hobbs

    No preview · Conference Paper · Nov 2015

  • No preview · Conference Paper · Nov 2015
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    ABSTRACT: Auger electron emitters such as (125)I have high linear energy transfer and short range of emission (< 10 μm), making them suitable for treating micrometastases while sparing normal tissues. We utilized a highly specific small molecule targeting the prostate-specific membrane antigen (PSMA) to deliver (125)I to prostate cancer (PC) cells. The PSMA-targeting Auger emitter [(125)I]DCIBzL was synthesized. DNA damage (via γH2AX staining) and clonogenic survival were tested in PSMA-positive PC3 PIP and PSMA-negative PC3 flu human prostate cancer cells after treatment with [(125)I]DCIBzL. Subcellular drug distribution was assessed with confocal microscopy employing a related fluorescent PSMA-targeting compound YC-36. In vivo antitumor efficacy was tested in nude mice bearing PSMA+ PC3 PIP or PSMA- PC3 flu flank xenografts. Animals were administered (intravenously) 3 mCi (111 MBq) of [(125)I]DCIBzL, 3 mCi of [(125)I]NaI, an equivalent amount of non-radiolabeled DCIBzL, or saline. After treatment with [[(125)I]DCIBzL, PSMA+ PC3 PIP cells exhibited increased DNA damage and decreased clonogenic survival when compared to PSMA- PC3 flu cells. Confocal microscopy of YC-36 showed drug distribution in the perinuclear area as well as the plasma membrane. Animals bearing PSMA+ PC3 PIP tumors had significant tumor growth delay after treatment with [(125)I]DCIBzL, with only one mouse reaching five times the initial tumor volume by 60 d post-treatment, compared to a median time to five times volume of less than 15 d for PSMA- PC3 flu tumors and all other treatment groups (P = 0.002 by log rank test). PSMA-targeted radiopharmaceutical therapy with the Auger emitter [(125)I]DCIBzL yielded highly specific antitumor efficacy in vivo, suggesting promise for treatment of PC micrometastases. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Full-text · Article · Jul 2015 · Journal of Nuclear Medicine

  • No preview · Article · Jun 2015 · Brachytherapy
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    ABSTRACT: Objectives The Programmed cell Death Ligand 1 (PD-L1) is part of an immune checkpoint system that is co-opted by tumor cells to suppress immune recognition of cancer. PD-L1 is expressed on tumor cells, tumor associated macrophages and other cells in the tumor microenvironment that can inhibit CD8+ T-cell effector function. Anti-PD-L1 antibodies (Ab) have been developed, and are currently in clinical trial against a variety of cancers. The aims of this study were to investigate the uptake of PD-L1 in tumors and normal tissues to evaluate the potential combination use of this Ab with radiopharmaceutical therapy, and to demonstrate the feasibility of PD-L1 imaging to identify tumors that are amenable to anti-PD-L1 therapy. Methods 6-week old healthy and tumor bearing female neu-N mice were injected i.v. with 10 µCi 111In labeled anti-PD-L1 Ab. The mice were sacrificed at 1, 24, 72 and 240 h p.i, normal tissues and tumors were collected and measured with a gamma counter. Tumor bearing mice were injected i.v. with 200 µCi 111In labeled anti-PD-L1 Ab, and SPECT imaged 1, 24 and 72 h p.i. Results The anti-PD-L1 Ab showed clearance from blood and other normal tissues except for spleen, which showed an increase and peaked at 72 h p.i. The tumor reached an uptake of about 6 %ID/g at 72 h p.i. No cross-reactivity with kidneys was observed and the kidney showed lower uptake than the tumors at 24 h p.i. After 240 h p.i. only the spleen and liver had higher uptake of anti-PD-L1 Ab than the tumors. Transient uptake in marrow regions was observed that was consistent with the blood kinetics. This suggests that there is no specific uptake in the marrow. Conclusions The anti-PD-L1 Ab showed a higher uptake in the tumors than the kidneys and marrow, with the highest uptake in the spleen. The results show a potential of use of anti-PD-L1 labeled Ab, taking into account the effect from the Ab itself as well as the attached radionuclide.
    No preview · Conference Paper · Jun 2015

  • No preview · Conference Paper · Jun 2015

  • No preview · Conference Paper · May 2015

  • No preview · Conference Paper · May 2015
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    ABSTRACT: Prostate-specific membrane antigen (PSMA) is a recognized target for imaging prostate cancer. Here we present initial safety, biodistribution, and radiation dosimetry results with [(18)F]DCFPyL, a second-generation fluorine-18-labeled small-molecule PSMA inhibitor, in patients with prostate cancer. Biodistribution was evaluated using sequential positron-emission tomography (PET) scans in nine patients with prostate cancer. Time-activity curves from the most avid tumor foci were determined. The radiation dose to selected organs was estimated using OLINDA/EXM. No major radiotracer-specific adverse events were observed. Physiologic accumulation was observed in known sites of PSMA expression. Accumulation in putative sites of prostate cancer was observed (SUVmax up to >100, and tumor-to-blood ratios up to >50). The effective radiation dose from [(18)F]DCFPyL was 0.0139 mGy/MBq or 5 mGy (0.5 rem) from an injected dose of 370 MBq (10 mCi). [(18)F]DCFPyL is safe with biodistribution as expected, and its accumulation is high in presumed primary and metastatic foci. The radiation dose from [(18)F]DCFPyL is similar to that from other PET radiotracers.
    No preview · Article · Apr 2015 · Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging
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    ABSTRACT: Yttrium-86 (t1/2 = 14.74 h, 33% β(+)) is within an emerging class of positron-emitting isotopes with relatively long physical half-lives that enables extended imaging of biological processes. We report the synthesis and evaluation of three low-molecular-weight compounds labeled with (86)Y for imaging the prostate-specific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding (90)Y-labeled radio-therapeutics. Multi-step syntheses were employed in preparing (86)Y-4-6. PSMA inhi-bition constants (Ki) were evaluated by competitive binding assay. In vivo characterization using tumor-bearing male mice was performed by PET/CT for (86)Y-4-6 and by biodistribution studies of (86)Y-4 and (86)Y-6 out to 24 h post-injection. Quantitative whole-body PET scans were recorded to measure the kinetics for 14 organs in a male baboon using (86)Y-6. Compounds (86)Y-4-6 were obtained in high radiochemical yield and purity with specific radioactivities of > 83.92 GBq/μmol. PET imaging and biodistribution studies using PSMA+ PC-3 PIP and PSMA- PC-3 flu tumor-bearing mice revealed that (86)Y-4-6 had high site-specific uptake in PSMA+ PC-3 PIP tumor starting at 20 min post-injection and remained high at 24 h. Compound (86)Y-6 demon-strated the highest tumor uptake and retention, with 32.17 ± 7.99 and 15.79 ± 6.44 %ID/g at 5 h and 24 h, respectively. Low activity concentrations were associated with blood and normal or-gans, except for kidney, a PSMA-expressing tissue. PET imaging in baboon reveals that all or-gans have a two-phase (rapid and slow) clearance, with the highest uptake (8 %ID/g) in kidneys at 25 min. The individual absolute uptake kinetics were used to calculate radiation doses using the OLINDA/EXM software. The highest mean absorbed dose was received by the renal cortex, with 1.9 mGy per MBq (86)Y-6. Compound (86)Y-6 is a promising candidate for quanti-tative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future (90)Y or other radiometal(s) that could employ a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of 6. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
    Full-text · Article · Feb 2015 · Journal of Nuclear Medicine
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    Lishui Cheng · Robert F. Hobbs · George Sgouros · Eric C. Frey
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    ABSTRACT: Purpose: Three-dimensional (3D) dosimetry has the potential to provide better prediction of response of normal tissues and tumors and is based on 3D estimates of the activity distribution in the patient obtained from emission tomography. Dose-volume histograms (DVHs) are an important summary measure of 3D dosimetry and a widely used tool for treatment planning in radiation therapy. Accurate estimates of the radioactivity distribution in space and time are desirable for accurate 3D dosimetry. The purpose of this work was to develop and demonstrate the potential of penalized SPECT image reconstruction methods to improve DVHs estimates obtained from 3D dosimetry methods.
    Full-text · Article · Nov 2014 · Medical Physics

  • No preview · Article · Oct 2014 · Journal of Nuclear Medicine

  • No preview · Article · Oct 2014 · Journal of Nuclear Medicine
  • George Sgouros · David M Goldenberg
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    ABSTRACT: Precision medicine is the selection of a treatment modality that is specifically tailored to the genetic and phenotypic characteristics of a particular patient's disease. In cancer, the objective is to treat with agents that inhibit cell signalling pathways that drive uncontrolled proliferation and dissemination of the disease. To overcome the eventual resistance to pathway inhibition therapy, this treatment modality has been combined with chemotherapy. We propose that pathway inhibition therapy is more rationally combined with radiopharmaceutical therapy (RPT), a cytotoxic treatment that is also targeted. RPT exploits pharmaceuticals that either bind specifically to tumours or accumulate by a broad array of physiological mechanisms indigenous to the neoplastic cells to deliver radiation specifically to these cells. Consistent with pathway inhibition therapy and in contrast to chemotherapy, RPT is well tolerated. However, the potential of RPT has not been fully exploited; for the most part, treatment has been implemented without using the ability to customise RPT by imaging and deriving individual patient tumour and normal organ radiation absorbed doses. These are more closely related to biological response and their determination should enable RPT treatment administration to maximum therapeutic benefit by treating to normal organ tolerance or demonstrating futility via tumour dosimetry. This is the essence of precision medicine.
    No preview · Article · Jun 2014 · European journal of cancer (Oxford, England: 1990)
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    George Sgouros · Robert F Hobbs · Diane S Abou
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    ABSTRACT: Radiopharmaceutical therapy (RPT) is a treatment modality that involves the use of radioactively labeled targeting agents to deliver a cytotoxic dose of radiation to tumor while sparing normal tissue. The biologic function of the target and the biologic action of the targeting agent is largely irrelevant as long as the targeting agent delivers cytotoxic radiation to the tumor. Preclinical RPT studies use imaging and ex vivo evaluation of radioactivity concentration in target and normal tissues to obtain biodistribution and pharmacokinetic data that can be used to evaluate radiation absorbed doses. Since the efficacy and toxicity of RPT depend on radiation absorbed dose, this quantity can be used to translate results from preclinical studies to human studies. The absorbed dose can also be used to customize therapy to account for pharmacokinetic and other differences among patients so as to deliver a prespecified absorbed dose to the tumor or to dose-limiting tissue. The combination of RPT with other agents can be investigated and optimized by identifying the effect of other agents on tumor or normal tissue radiosensitivity and also on how other agents change the absorbed dose to these tissues. RPT is a distinct therapeutic modality whose mechanism of action is well understood. Measurements can be made in preclinical models to help guide clinical implementation of RPT and optimize combination therapy using RPT.
    Preview · Article · May 2014
  • George Sgouros · Robert F Hobbs
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    ABSTRACT: Radiopharmaceutical therapy (RPT) involves the use of radionuclides that are either conjugated to tumor-targeting agents (e.g., nanoscale constructs, antibodies, peptides, and small molecules) or concentrated in tissue through natural physiological mechanisms that occur predominantly in neoplastic or otherwise targeted cells (e.g., Graves disease). The ability to collect pharmacokinetic data by imaging and use this to perform dosimetry calculations for treatment planning distinguishes RPT from other systemic treatment modalities such as chemotherapy, wherein imaging is not generally used. Treatment planning has not been widely adopted, in part, because early attempts to relate dosimetry to outcome were not successful. This was partially because a dosimetry methodology appropriate to risk evaluation rather than efficacy and toxicity was being applied to RPT. The weakest links in both diagnostic and therapeutic dosimetry are the accuracy of the input and the reliability of the radiobiological models used to convert dosimetric data to the relevant biologic end points. Dosimetry for RPT places a greater demand on both of these weak links. To date, most dosimetric studies have been retrospective, with a focus on tumor dose-response correlations rather than prospective treatment planning. In this regard, transarterial radioembolization also known as intra-arterial radiation therapy, which uses radiolabeled ((90)Y) microspheres of glass or resin to treat lesions in the liver holds much promise for more widespread dosimetric treatment planning. The recent interest in RPT with alpha-particle emitters has highlighted the need to adopt a dosimetry methodology that specifically accounts for the unique aspects of alpha particles. The short range of alpha-particle emitters means that in cases in which the distribution of activity is localized to specific functional components or cell types of an organ, the absorbed dose will be equally localized and dosimetric calculations on the scale of organs or even voxels (~5mm) are no longer sufficient. This limitation may be overcome by using preclinical models to implement macromodeling to micromodeling. In contrast to chemotherapy, RPT offers the possibility of evaluating radiopharmaceutical distributions, calculating tumor and normal tissue absorbed doses, and devising a treatment plan that is optimal for a specific patient or specific group of patients.
    No preview · Article · May 2014 · Seminars in nuclear medicine

Publication Stats

6k Citations
1,046.33 Total Impact Points

Institutions

  • 2004-2015
    • Johns Hopkins University
      • • Division of Nuclear Medicine
      • • Department of Medicine
      • • Department of Radiology
      Baltimore, Maryland, United States
    • Johns Hopkins Medicine
      • Division of Nuclear Medicine
      Baltimore, Maryland, United States
  • 2010
    • University of Lausanne
      Lausanne, Vaud, Switzerland
  • 1983-2010
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Medical Physics
      • • Department of Medicine
      New York, New York, United States
  • 2002
    • Philipps University of Marburg
      • Klinik für Strahlendiagnostik (Marburg)
      Marburg, Hesse, Germany
  • 2001
    • CUNY Graduate Center
      New York, New York, United States
  • 1999
    • University of California, Davis
      Davis, California, United States
  • 1994
    • Austin Health
      • Department of Nuclear Medicine and Centre for PET
      Melbourne, Victoria, Australia
  • 1990
    • New York Downtown Hospital
      New York, New York, United States
  • 1985
    • Cornell University
      Итак, New York, United States